Penicillins

ABSTRACT

DISCLOSED AR SEMI-SYNTHETIC PENICILLINS HAVING A BROAD SPECTRUM OF ANTIBACTIRIAL ACTIVITY OF THE GENERAL FORMULA

United States Patent [1 1 Ferres et al.

[ 1 Dec. 16, 1975 PENICILLINS [75] Inventors: Harry Ferres, l-lorsham; Adrian Victor Kemmenoe, Westcott; Desmond John Best, Sutton, all of England [73] Assignee: Beecham Group Limited, England [22] Filed: Jan. 22, 1975 [2]] Appl. No.: 543,070

Related U.S. Application Data [62] Division of Ser. No. 466,184, May 3, 1974.

[30] Foreign Application Priority Data [56]' I References Cited UNITED STATES PATENTS 3,340,252 9/1967 Album etal 260/2391 12/1969 McGregor 260/2391 Primary Exam iner-Gerald A. Schwartz ABSTRACT Disclosed ar semi-synthetic penicillins having a broad spectrum of antibactirial activity of the general formula 9 Claims, No Drawings PENICILLINS This is a division of application Ser. No. 466,184 filed May 3, 1974.

This invention relates to penicillins which have, in general, a broad spectrum of antibacterial activity, being active against many species of Gram-positive and Gram-negative bacteria. They are thus useful as therapeutic (and, to a lesser extent, prophylactic) agents in animals, including man and poultry. The invention further relates to methods for the preparation of these penicillins and to their use in therapy.

Although there are now available a number of semisynthetic penicillins having what is known as broadspectrum activity, no single penicillin is yet available which has a clinically useful level of antibacterial activity against all the pathogenic organisms encountered in clinical practice. The search thus continues for broadspectrum penicillins which have advantages, either in improved antibacterial effectiveness or wider spectrum of activity, over the available penicillins.

According to the present invention there is provided a penicillin of formula (I) or a pharmaceutically acceptable salt or ester thereof:

R- cuco-mr s COOH (ll) C--R (Ill) wherein R is amino, monoor ,di-alkylamino wherein the alkyl groups contain from 1 to 4 carbon atoms, cyclohexylamino, hydrogen, alkyl, having from 1 to 4 carbon atoms, or phenyl and R is aminoor monoor dialkylamino wherein the alkyl groups contain from 1 to 4 carbon atoms, or cyclohexylamino.

The group R may be, for example, phenyl, 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 4-nitrophenyl, 4-

.chlorophenyl, 4-fluorophenyl, 4-methoxy-phenyl, 4- arninophenyl, 2-thienyl, 3-thienyl, cyclopropyl, .cyclohexyl, cyclohexal ,4-dienyl, iso-propyl or methyl.

2 The group R may, for example, be hydrogen, phenyl,

" 4-hydroxyphenyl, 4-nitrophenyl, 4-chlorophenyl, 4-

amino, hydrogen, methyl, ethyl, nor isopropyl, n-, sec,

or tert-butyl, or phenyl.

The group R may for example, be amino, methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, isopropylamino, tert-butylamino, nbutylamino or cyclohexylamino.

Preferably R is phenyl, 4-hydroxyphenyl, or 3-thienyl.

Preferably R is phenyl, 4-hydroxyphenyl, 4- chlorophenyl, 4-fluorophenyl, 4-nitrophenyl, 3-indolyl, or methylthiomethyl.

Preferably R is hydrogen.

Preferably R is amino or hydrogen.

Preferably R is amino.

Preferably the carbon atom to which the group R in formula (I) is attached is in the D configuration.

Preferably the carbon atom to which the group R in formula (I) is attached is in the D configuration.

Examples of suitable salts of compounds (I) include the sodium, potassium, calcium, magnesium or aluminium salts, and ammonium or substituted ammonium salts, for example those with trialkylamines such as triethylamine, procaine, dibenzylamine, triethanolamine, l-ephenamine, ethylpiperidine, and other amines which have been used to form salts with benzylpenicillins. In the case of compounds (I) which contain a basic nitrogen site in the side chain, acid addition salts may also be formed. Such salts include, for example, inorganic salts such as the sulphate, nitrate, phosphate, borate, thiocyanate, and hydrohalides, e.g. hydrochloride, hydrobromide and hydroiodide, and organic salts such as the acetate, oxalate, tartrate, malate, citrate, succinate, benzoate, ascorbate. and methanesulphonate.

Examples of suitable pharmaceutically acceptable esters include those which break down readily in the human body to leave the parent acid, e.g. acyloxyalkyl esters such as acetoxymethyl, pivaloyloxymethyl, aacetoxyethyl, a-acetoxybenzyl and a-pivaloyloxymethyl esters, and alkoxycarbonylalkyl esters such as methoxy carbonyloxymethyl esters. Other suitable esters of this readily hydrolysable type include lactone, thiolactone, and dithiolactone esters (i.e. compounds of formula (I) wherein the 3-carboxy group is esterified to produce a grouping of formula:

wherein X and Y are oxygen or sulphur and Z is a divalent hydrocarbon group), especially the phthalidyl and substituted phthalidyl esters e.g. 5,6-dimethoxyphthalidyl ester.

The compounds of this invention may be prepared by reacting 6-aminopenicillanic acid or a salt, ester or silyl derivative thereof with an N-acylating derivative of an acid of formula (IV) in which any reactive substituents may be blocked, wherein R, R, R and R are as defined in formula (I) and then, if necessary, carrying out one or more of the following steps (i) removing any silyl groups by hydrolysis or alcoholysis, (ii) converting an ester compound to a free acid or salt (iii) converting a salt to a free acid or a free acid to a salt (iv) removing any blocking groups to release the desired functional substituent (v) converting a free acid compound to an ester compound.

By the term silyl derivative used in connection with 6-amino-penicillanic acid (6-APA) we mean the product of the reaction between 6-APA and a silylating agent such as a halotrialkylsilane, halodialkylsilane, a

halotrialkoxysilane, a dihalodialkoxysilane or a corresponding aryl or aralkyl silane and compounds such as hexamethyldisilazane. In general, halotrialkylsilanes are preferred, especially trimethylchlorosilane.

A reactive N-acylating derivative of the acid (IV) is employed in the above process. The choice of reactive derivative will of course be influenced by the chemical nature of the substituents in the acid. Thus, when the acid contains only acid stable groups, an acid halide is a suitable N-acylating derivative, preferably the acid chloride.

Such reagents would, however, be avoided when an acid labile group was present in the acid (IV). In such cases a suitable N-acylatin g derivative is a mixed anhydride. For this purpose particularly convenient mixed anhydridesare the alkoxyformic anhydrides.

However, with both the acid chloride and mixed anhydride N-acylating agents we have found that some racemisation may take place. To minimise such unwanted racemisation, we prefer to use an activated ester as the N-acylating agent. Such activated esters, for example the ester formed with l-hydroxybenzotriazole or, preferably, N-hydroxysuccinimide, may be prepared in situ by the reaction of the acid with the appropriate hydroxy compound in the presence of a carbodiimide, preferably dicyclohexylcarbodiimide.

Other reactive N-acylating derivatives of the acid (II) include the reactive intermediate formed by reaction in situ with a carbodiimide or carbonyldiimidazole, but the literature on the preparation of semisynthetic penicillins contains examples of other reactive N-acylating derivatives of acids suitable for coupling to 6-APA.

It will be understood, of course, that where a free acid of type (I) or a salt thereof is desired, it may be convenient to carry out the acylation reaction using an ester of 6-APA, and then to remove the ester group. Vice versa, if an ester is required, it may be convenient to carry out the acylation reaction, using 6-APA or a salt thereof and thereafter to esterify the free acid.

In the above process, if it is necessary to block any reactive substituents in the acid (IV), conventional chemical blocking groups are known. Thus, if desired, any free amino groups may be blocked by conversion to benzyloxycarbonylamino groups, or the amino group thereof.

wherein R is as defined in formula (I) and in which any reactive substituents may be blocked, with an N-acylating derivative of an acid of formula (IV) R-CH-CO-NH co'oa wherein R, R and R are as defined in formula (I), and if necessary, carrying out one or more of the following steps (i) removing any silyl groups by hydrolysis or alcoholysis, (ii) converting an ester compound to a free acid or salt thereof (iii) converting a salt to a free acid or a free acid to a salt (iv) removing any blocking groups to release the desired functional substituents (v) converting a free acid compound to an ester compound.

The remarks made earlier with respect to silyl derivatives, N-acylating derivatives, and blocking groups, also apply to this process.

The compounds of this invention wherein R is a group of formula (II) may also be prepared by reacting a compound of formula (VII) or a salt, ester or silyl derivative thereof:

R-CH-CO-NH wherein R, R, R and R are as defined in formula (I) and wherein any reactive substituents may be blocked, with cyanate ion, a C alkyl isocyanate, cyclohexyl isocyanate, a formylating agent or an N-acylating derivative of an acid R COOI-I wherein R is phenyl or an alkyl group having from I to 4 carbon atoms, followed, if necessary, by one or more of the following steps (i) removing any silyl groups by alcoholysis or hydrolysis, (ii) converting an ester compound to a free acid or salt thereof, (iii) converting a salt to a free acid or a free acid to a salt (iv) removing any blocking groups to release the desired functional substituent, (v) converting a free acid compound to an ester .compound.

consists in generating the desired group R from the free amino group in compound (VII). The reaction of amino compounds with cyanate ion and isocyanates to produce ureas and substituted ureas is well known. Likewise the formylation of amino compounds (e.g. using formic acid and acetic anhydride) is well known. Similarly, the acylation of amino compounds is extremely well known, and suitable N-acylating derivatives of acids have been discussed hereinbefore.

The compounds of this invention are broad spectrum penicillins, i.e. penicillins which not only have activity against Gram-positive bacteria, but also against a number of clinically important Gram-negative organisms. The preferred compounds of this invention are active against such important organisms as Pseudomonas spp. against which the most well known broad-spectrum penicillin (6 D )a-amiriophenylacetamido ]penicillanic acid ampicillin) is normally inactive. Moreover the preferred compounds of this invention are about as active as 6[ D )a-carboxy-3- thienylacetamido] penicillanic acid against Pseudomonas spp., this latter compound being the most active of the known penicillins against those organisms. Several of the preferred compounds of this invention have minimum inhibitory concentrations of from 5 12.5 pg/ml against some B-lactamase producing strains of staphylococci, against which the majority of known broad spectrum penicillins are only marginally effective. The preferred compounds of this invention are not greatly serum-bound, and are not markedly inactivated by serum. 1

The penicillins of this invention show the characteristic lack of toxicity of penicillins generally. They may be administered by parenteral injection. The daily dose will depend on the identity of the penicillin and severity of infection. With the preferred compounds of this invention, a suitable average daily dose for an adult would be in the range of 100mg to 5000mg. An average single dose for an adult would be from mg to 500 lhe followingExamples illustrate the preparation of some of the compounds of this invention:

R-CH-CO-Nil l t CH its 5 o coon co In the following Examples amoxycillin is the approved name for 6[D-a-amino-p-hydroxyphenylacetamidolpenicillanic acid and ampicillin is the approved name for 6[D-a-aminophenylacetamido]penicillanic acid. Epicillin is the approved name for [D-oz-amino -cyclohexa-l,4-

dienylacetamido]penicillanic acid. All temperatures are in C. All biochromatograms were run in butanol/ethanol/water. All compounds were made by one of the following generally applicable methods.

The majority of the starting materials used in the following Examples are known. However, the following literature references describe generally applicable methods which may be used to prepare the starting materials:

URElDO-AC IDS DAKlN I Amer.Chem. J. 44 54 ANDREASCH 1 Monats. 23. 805

NEVILLE, MGEE I Can..I.Chem. 41, 2123-9 (1963) WIELAND I I Bio.Z. 38, 389, Ann.3.

DAVIS, BLANCHARD J.Amer.Chem.Soc. S1, 1797 LEUTHARDT,BRUN- 1 Helv.Chim.Acta. 30, 964-5 (1947) NER SUBSTITUTED URElDO-ACIDS BALL, SKINNER, Texas Rept. BioLMed. 21(2) SHIVE 188-75 (1963) BRlTlSH PATENTS 1301961/2. GUANlDlNO-ACIDS KAPFHAMMER, Z. PhysioLChem. 225, l-12, (1934) MlLLER RADKA PANT I ibid 335, 272-4 (1964) FRAMM, KAPELLER Ann. (1925) 442, 144

HABEL Z Can.J.Biochem. Physiol. 38, 493 (1960) RAMSAY Ber. 41, 4390 SHEEHAN, YOUNG I J.Amer.Chem.Soc. (1958), 80, 1154 Method A A solution of the guanidino-acid, hydrochloride (5m. mole) in dry dimethylformamide (5 ml) was added over 10 mins. to a stirred solution of phthalid-3-yl D-aaminophenyl-acetamidopenicillanate (5 m. mole) and N,N -dicyclohexylcarbodi-imide (5.8 m. mole) at 0C in dry methylene dichloride.

After stirring at 0C for 30 mins. and 1% hours at ambient temperatures, the mixture was cooled to l0C and the dicyclohexylurea removed by filtration.

The solution was washed with dilute hydrochloric acid (pH 1.5), water, and brine and the dried solution concentrated to low volume in vacuo to induce crystallisation. The filtered solid was dried under vacuum over phosphorus pentoxide.

Method B Ureido- (or substituted-ureido-) acid (0.01 mole) in dry acetone (60 ml) at l 0C was treated with triethylamine (ca. 0.015 mole) and iso-butylchloroformate (0.01 mole) and stirred at -10C for not more than 30 mins. D-a-aminophenylacetamidopenicillanic acid, trihydrate (0.01 mole) in water (60 ml) was treated with triethylamineto give a clear solution (pl-l 8.4). Acetone (60 ml) was added and the solution cooled to 0C.

The mixed anhydride solution cooled to 40C was filtered through Celite into the stirred penicillin solution and the mixture allowed to warm slowly to room temperature over 20 mins.

The acetone was evaporated in vacuo and the aqueous residue washed well with ether and then acidified to pl-l2 under a layer of ethyl acetate with 5N hydrochloric acid.

The product was obtained either as the free acid by filtration of the aqueous/ethyl acetate mixture or by precipitation from the ethyl acetate solution with potassium or sodium 2-ethylhexoate to give the corresponding alkali-metal salt.

Method Bi. As B, but using N-methylmorpholine instead of triethylamine in the preparation of the mixed anhydride.

Method Bii. As B, but using D-a-amino-(p-hydroxyphenyl)-acetamidopenicillanic acid, trihydrate instead of D-a-aminophenylacetamidopenicillanic acid, trihydrate.

Method Biii. As Bii., but using N-methylmorpholine instead of triethylamine in the preparation of the mixed anhydride.

Method Biv. As Bi., but using D-a-amino-(3-thienyl)- acetamidopenicillanic acid instead of D-a-aminophenylacetamidopenicillanic acid, trihydrate.

Method Bv. As Bi., but using D-a-amino-(1,4-

cyclohexadienyl)-acetamidopenicillanic acid instead of D-a-aminophenylacetamidopenicillanic acid, trihydrate.

Method Bvi. As Bi., but using ethylchloroformate instead of iso-butyl chloroformate and D-a-aminocyclopropylacetamidopenicillanic acid, trihydrate.

Method Bvii. As Bi., but using D-ozaminovaleramidopenicillanic acid instead of Daaminophenylacetamidopenicillanic acid, trihydrate.

Method Bviii. As Bi., but using ethylchloroformate instead of iso-butyl chloroformate, and D-a-amino- (2-thienyl)-acetamidopenicillanic acid instead of D-a-aminophenylacetamidopenicillanic acid, trihydrate.

Method Bix. As Bi., but using D-a-amino-B-phenylpropionamidopenicillanic acid instead of D-a-aminophenylacetamidopenicillanic acid.

(No Method C) Method D Amino-penicillin (5 m.moles) in dry dimethylformamide (100ml) was treated with triethylamine (l2 m.moles) and stirred to give a clear solution. Sulphur trioxide-triethylamine complex (6 m.moles) was added portionwise over 5 mins. at room temperature and stirred for 1 hour. A solution of potassium 2-ethyl hexoate (ca m.moles) in dry acetone (150ml) was added and a white solid separated.

After further dilution with acetone (200ml) the solid was filtered, washed with acetone and then stirred in dry ether for mins. to remove any residual dimethylformamide. The solid was filtered and dried in vacuo. Method E Anhydrous D-a-aminophenylacetamidopenicillanic acid (5m. mole) in dry methylene dichloride (50 ml) was treated with triethylamine (-10 m. mole) to give a clear solution. Trimethylsilyl chloride (10 m. mole) was added and the mixture refluxed under nitrogen for 1 hour, then cooled to 0C.

a-Guanidino-acid (5 n1. mole) was dissolved in dry dimethylformamide (55ml) and dry dimethylformamide (5ml.) and dry methylene dichloride (50 ml) added, cooled to 0C and stirred for 5 mins. with dicyclohexyl-carbodi-imide (5.5 m. mole). The bis-trimethylsilylated penicillin was added and stirred at 0C for 1 hour. The mixture was then cooled to 20C and the 8 dicyclohexylurea removed by filtration. The filtrate was evaporated to dryness in vacuo and the residue dissolved in acetone (20ml)/water (20 ml) and the pH adjusted to 2.5 with 5N hydrochloric acid. After stirring at pH 2.5 for 25 mins. the acetone was removed in vacuo and any solid filtered off. The residual aqueous solution was freeze dried and the resultant solid treated with water at pH 2. The product was filtered and dried.

Method F Dicyclohexylcarbodi-imide (5.5 m. mole) was added to a stirred solution of N-substituted-amino acid (5 m. mole) in dry acetone (20 ml) at 0C. The mixture was stirred for 15 mins. at 0-5C and then left in the refrigerator overnight.

D-a-Aminophenylacetamidopenicillanic acid, trihydrate (5m. mole) was dissolved in acetone l0 ml)/water 10 ml) with triethylamine (0.7 ml) and the hydroxysuccinimide ester filtered in, through Celite. After stirring for 45 mins. the acetone was removed in vacuo, leaving a gelatinous mass. Acidification with 5N hydrochloric acid in aqueous ethyl acetate gave the product as the free acid (sometimes only after concentration of the ethyl acetate layer and treatment with ether) or as the salt by treatment of the washed and dried ethyl acetate layer with sodium or potassium 2-ethyl hexoate.

Method Fi. As F, but the hydroxysuccinimide ester formed in dry dimethylformamide (or dimethylformamide diluted with acetone).

Method Fii. As F, but the hydroxysuccinimide ester formed in dry 1,2-dimethoxyethane.

Method Fiii. As Fi., but the penicillin dissolved in acetone/chloroform, the product coming out of solution as the amine salt.

EXAMPLE 1 D-a-[D-B-(p-Hydroxyphenyl)-a-ureidopropionamido]phenylacetamido penicillanic acid Prepared by method Bi), from D-B-(p-Hydroxyphenyl)-a-ureidopropionic acid.

Yield: 68%

max (KBr): 3350, 1770, 1650, 1515, 1230 and 700cm 8[(CD SO]: 1.44 (3H. s.gem methyl); 1.57 (3H. s. gem methyl); -2.8 (2H. m. I LI CH 4.29 (1H. s. C-3 proton); -4.5 (1H. m. g H CH 5.35 5.87 (5H. m. B-lactams,

Nncoi m 6.27 (1H. d. NgcoNHm; 6.67

s E H9GCR2-); 6.99 (ZHAEQCHZ);

EXAMPLE 7 Sodium D-a-[ DL-a-formamido-y-methylthiobutyramido phenylacetamido penicillanate Prepared by Method B, using N-Formyl-DL-methionine and ampicillin, isolated as the sodium salt after treatment with sodium 2-ethyl hexoate.

Yield: 63%.

max (KBr): 3300 (broad), 1780, 1732, 1645, 1525, 1.302, 1225 and 700 cm.

8[(CD SO]: 1.46 (3H. s. gem methyl); 1.55 (3H. s. gem methyl); 1.7 2.2 (2H. m. CH SCH CQ CH 2.05 (3H. d. C S); 2.3 2.7 (2H. m. CH S CQ CH 4.23 (1H. s. C-3 proton); 4.70 (1H. m.

NHCHO); 5.3 5.9 (3H. m. B-lactams and PhCg 7.37 (H. m. aromatics); 8.08 (1H. s. NHCHO); 8.31,

8.60 and 9.00 (3 X 1H. d. -CONli*-). Removable in D10.

NH OH assay: 100% Biochromatogram: Single zone at R 0.40.

EXAMPLE 8 D-a-[DL-B-(p-Chlorophenyl)-a-ureidopropionamido]-(p-hydroxyphenyl)-acetamidopenicillanic acid.

Prepared by Method Bii) from DL-B-(P-Chlorophenyl-a-ureidopropionic acid and amoxycillin.

Yield: 45%.

max (KBr): 3360, 1770, 1650, 1514 and 1230 cm".

5[(CD SO]: 1.42 (3H. s. gem dimethyl); 1.58 (3H. s. gem dimethyl); 2.86 (2H. m. Cg- ,CH 4.26 1H. s. C-3 proton); 4.55 (1H. m. CH CQ 5.58 (5H.

m. B-lactams,

NHCON ll 6.24 (1H. m. NQCONHJ); 6.78 and 7.27

8.53 (1H. m. CONlf); 9.04 (1H. m. CONE). Removable in D 0.

Biochromatography: Rf 0.42

Analysis: C H N O SCl required: C, 52.93; H, 4.75; N, 11.87; S, 5.43; Cl, 6.02. Found: C, (50.23); H, 4.79; N, 11.13; S, 5.32; Cl, 5.97.

EXAMPLE 9 D-a-[DL-,8( p-Fluorophenyl )-a-ureidopropionamido]- phenylacetamido penicillanic acid Prepared by method B from DL-B-(p-fluorophenyha-ureidopropionic acid and ampicillin.

Yield: 42%.

max (KBr): 3360, 1773, 1651, 1510, 1226 and 720 cm.

8[(CD SO]: 1.42 (3H. s. gem methyl); 1.57 (3H. s. gem methyl); 1.57 (3H. s. gem methyl); 2.87 (2H. m. C CH 4.24 (1H. s. C-3 proton); 4.56 (1H. m. CH CQ 5.65 (5H. m. B-lactams, a-proton, NH- CONQJ 6.27 (1H. d. NgCONl-lf); 7.24 (9H. m. Pg

8.62 (1H. m. CONQ-*); 9.17 (1H. m. CON*). *Removable in D20.

Biochromatography: 1 Spot at R 0.42.

EXAMPLE l0 D-a-[DL-B-(p-Chlorophenyl)-a-ureidopropioniamido]phenylacetamido penicillanic acid Prepared by Method B, from DL-B-(p-chlorophenyl)-a-ureidopropionic acid.

Yield: 38%

max (KBr): 3360, 1770, 1650, 1514 and 1230 cm.

8[(CD SO]: 1.40 (3H. s. gem methyl); 1.56 (3H. s. gem methyl); 2.85 (2H. m. CH Cl-l 4.25 (1H. s. C-3 proton); 4.55 (1H. m. -CH CQ 5.58 (5H. m.

B-lactams,

NHCONQQ; 6.25 (1H. m. NQCONHQ; 7.30 (9H. m. aromatic protons) 8.53 (1H. m. CON fl 9.00 (1H. m. CONQ).

NH OH Assay: 94%.

Biochromatography: 1 zone at R 0.59.

EXAMPLE 1 1 CO l R CH C R wherein R is phenyl, hydroxyphenyl, halophenyl, nitrophenyl,

alkoxyphenyl having 1-3 carbon atoms in the alkoxy part, aminophenyl, 2- or 3-thienyl, cycloalkyl having 3-7 carbon atoms in the cyclo part, cycloalkenyl having -7 carbon atoms in the cyclo part, or alkyl having l-4 carbon atoms;

R is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert.-butyl, n-pentyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylthio, ethin which R is amino, monoor di-alkylamino having l-4 carbon atoms in the alkyl part, cyclohexylamino, hydrogen, alkyl of l-4 carbon atoms or phenyl, and R is amino, monoor di-alkylamino having l-4 carbon COOH atoms in the alkyl part or cyclohexylamino;

R is hydrogen or alkyl of l-3 carbon atoms; or a pharmaceutically acceptable salt or a pharmaceutically acceptable hydrolyzable ester which converts to the freeacid form in vivo.

2. A penicillin of claim 1 wherein the carbon atom attached to R is in the D-configuration.

3. A penicillin of claim 1 wherein the carbon atom attached to R is in the D-configuration.

4. A penicillin of claim 1 wherein R is phenyl, 4- hydroxyphenyl or 3'thienyl.

5. A penicillin of claim 1 wherein R is hydrogen.

6. A penicillin of claim 1 wherein; when R is (II), R is amino or hydrogen or, when R is (III), R is amino.

7. A penicillin of claim 1 which is 6( D,0z-[ D,a-ureido-a-methylthiobutyramido phenylacetamido) penicillanic acid;

6( D,a-[ D,a.-forrnamido-B-methylthiobutyramido phenylacetamido)penicillanic acid.

8. A penicillin of claim 1 wherein the ester is phthalidyl, 5,6-dimethoxyphthalidyl, pivaloyloxymethyl or acetoxymethyl.

9. A penicillin of claim 1 wherein the salt is a base addition or acid addition salt. 

1. A PENICILLIN OF FORMULA (I):
 2. A penicillin of claim 1 wherein the carbon atom attached to R is in the D-configuration.
 3. A penicillin of claim 1 wherein the carbon atom attached to R2 is in the D-configuration.
 4. A penicillin of claim 1 wherein R is phenyl, 4-hydroxyphenyl or 3-thienyl.
 5. A penicillin of claim 1 wherein R3 is hydrogen.
 6. A penicillin of claim 1 wherein, when R2 is (II), R5 is amino or hydrogen or, when R2 is (III), R6 is amino.
 7. A penicillin of claim 1 which is 6(D, Alpha -(D, Alpha -ureido- Alpha -methylthiobutyramido)-phenylacetamido) penicillanic acid; 6(D, Alpha -(D, Alpha -formamido- Beta -methylthiobutyramido)-phenylacetamido)penicillanic acid.
 8. A penicillin of claim 1 wherein the ester is phthalidyl, 5,6-dimethoxyphthalidyl, pivaloyloxymethyl or acetoxymethyl.
 9. A penicillin of claim 1 wherein the salt is a base addition or acid addition salt. 